The NIMH?s RFA-Suicide Prevention in Emergency Medicine Departments recognizes the emergency department (ED) as an important setting to increase suicide detection and prevention efforts but observes that evidence-based practice guidelines do not exist. In response, we have designed the ED Safety Assessment and Follow-up Evaluation (EDSAFE) trial. Two inter-related studies will be conducted using a quasi-experimental design appropriate for studying systems-based change. The studies will share three phases of data collection: Treatment as Usual, Screening Alone, and Intervention. During each phase, 472 suicidal patients (1,416 total) will be enrolled and followed using multiple methods for 12 months. The first study, the Screening Outcome Study, will use data collected during the first two phases (Treatment as Usual and Screening Alone). Primarily, it will focus on testing a practical approach to screen ED patients for suicidal ideation and behavior and will assess its impact on suicide detection, process outcomes, and suicide behaviors. The second study, the Care-chain Evaluation Study, will use data collected during the last two phases (Screening Alone and Intervention). Primarily, it will evaluate the impact of a multi-component intervention on suicide outcomes. The intervention blends conceptual underpinnings from screening, brief intervention, and referral to treatment (SBIRT) models for health behaviors with empirically grounded strategies for suicide prevention. It will involve (1) Question, Refer, Persuade counseling provided by the treating nurse, (2) incorporation of a Comprehensive Suicide Management Protocol into clinical practice, and (3) post-discharge telephone counseling. Our overarching hypotheses will be tested using a combination of both studies. We predict that screening will improve detection of suicidal ideation, and the intervention will enhance the quality of care and reduce suicide outcomes. Our studies offer the following innovations and strengths: (1) inclusion of eight general medical EDs representative of broad geographic regions, patient demographics, and catchment areas (i.e., urban, suburban, rural); (2) use of the EMNet, which was awarded a best practice designation by the NIH-funded Inventory and Evaluation of Clinical Research Networks (IECRN); (3) a structured intervention that is empirically based, practical, and flexible enough to accommodate a full spectrum of suicidal ideation and behavior; (4) stratification of the sample and planned analyses to examine whether the intervention?s effectiveness differs based upon baseline suicide risk; (5) a multi-method outcome attainment strategy; and, (6) a multi-component evaluation that will help determine effectiveness, feasibility, and sustainability. Public Health Relevance: The lack of implementation of screening and brief interventions for suicidal ideation in the ED setting is a significant problem with far-reaching consequences, including excess morbidity and premature mortality. Our study focuses on examining the effectiveness, feasibility, and sustainability of a multi-component screening and intervention for suicide within general ED settings. Our study should hold important implications for a variety of stakeholders, including patients, family members, healthcare providers, financial managers, health insurers, administrators, and policy makers.